PROJECT SUMMARY Bioenergetic dysfunction occurs in Alzheimer?s disease (AD), and represents a potential AD therapeutic target. For these reasons, we founded Aerobyx, LLC. The goal of Aerobyx is to develop drugs that specifically target brain bioenergetic fluxes, and to use those drugs to treat persons with AD. Our strategy emphasizes fundamental biochemical principles such as the law of mass action, and additionally exploits redox ratios (in particular NAD+/NADH coupling) that gate some bioenergetic fluxes. Our overarching hypothesis is that enhancing brain respiration flux, glycolysis flux, or both will benefit AD patients. This phase I SBIR will specifically advance development of two of our lead compounds, both of which are esters of oxaloacetate (OAA). Our interest in OAA derives from observations that OAA can concomitantly enhance both glycolysis and respiration fluxes, and a study performed in mice that found OAA activated brain mitochondrial biogenesis-promoting proteins, enhanced activity of the brain insulin signaling pathway, reduced neuroinflammation markers, and increased hippocampal neurogenesis. As OAA is unstable in solution, we stabilized it through esterification at its carboxyl ends, to molecules that can independently support bioenergetic metabolism. Under in vitro conditions these compounds perform as predicted, and in cultured cells enhance respiration. To develop further these compounds for clinical use, we will now increase compound synthesis to levels that can support in vivo studies, and obtain in vivo pharmacokinetic and pharmacodynamic data. Accordingly, we will dose mice with both compounds; measure blood, plasma, and brain levels of the parent compounds and their metabolites; and assess brain target engagement. Data generated during this phase I SBIR will inform a phase II SBIR project in which we perform comprehensive animal toxicity studies, and determine the effects of our compounds in an AD transgenic mouse model.